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Retinol-Binding Protein 4 Activates STRA6 Provoking Pancreatic β Cell Dysfunction in Type 2 Diabetes
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posted on 2020-11-16, 18:47 authored by Ada AdminAda Admin, Rong Huang, Xinxiu Bai, Xueyan Li, Xiaohui Wang, Lina ZhaoPancreatic β cell dysfunction plays a decisive role in
progression of type 2 diabetes. Retinol binding protein 4 (RBP4) is a prominent
adipokine in type 2 diabetes while its effect on β cell function remains
elusive and the underlying mechanisms are unknown. Here, we found that
elevated circulating RBP4 levels were inversely correlated with pancreatic β
cell function in db/db mice across different glycemic stages. RBP4
directly suppressed glucose stimulated insulin secretion (GSIS) in primary
isolated islets and INS-1E cells in a dose- and time-dependent manner.
RBP4-transgenic overexpressing mice (RBP4-Tg) showed a dynamic decrease of GSIS
which appeared as early as 8-week-old preceding the impairment of insulin
sensitivity and glucose tolerance. Islets isolated from RBP4-Tg mice showed a
significant decrease of GSIS. Mechanistically, we demonstrated that the stimulated by
retinoic acid 6(STRA6), RBP4’s only known specific membrane receptor, is
expressed in β cells and mediates the inhibitory effect of RBP4 on insulin
synthesis via JAK2/STAT1/ISL-1 pathway. Moreover, decreasing circulating RBP4
level could effectively restore β cell dysfunction and ameliorate hyperglycemia
in db/db mice. These observations revealed a role of RBP4 in pancreatic β cell
dysfunction which provided new insight into the diabetogenic effect of RBP4.